Endogenous Retroviruses as a Key Modulator of Immune Response to Cancer Therapies

Endogenous retroviruses (ERVs) are ancient deactivated viral elements that have integrated into the human genome over the course of millennia of evolution. ERVs are normally kept transcriptionally repressed, but recent evidence has demonstrated that ERV transcription can be upregulated in response to a variety of stimuli and pharmacological treatments. Furthermore, ERV transcription in the form of double-stranded RNA (dsRNA) was shown to upregulate a host of immune signaling pathways, with implications for the future of cancer therapy. In this study, we utilize the transcriptional corepressor KRAB-Associated Protein 1 (KAP1), a chromatin modulator responsible for suppressing ERV transcription sites, as a tool to investigate ERV expression in cancer therapy.

We demonstrate that radiotherapy, historically believed to mediate tumor cell repression through direct cell killing, can also upregulate ERV transcription, which stimulates downstream interferon production and interferon-stimulated genes through the MDA5/MAVS innate antiviral immunity pathway, a separate pathway from cGAS/STING signaling. KAP1 depletion enhances the effect of radiation, as ERV and interferon transcription is significantly upregulated. Additionally, KAP1 depletion enhances the effect of radiation-induced anti-tumor response in vivo in two separate tumor models. Our findings indicate a novel and understudied pathway of radiotherapy-induced tumor control.

We also demonstrate that KAP1 depletion is sufficient to provoke interferon signaling and immune effects. KAP1 depletion upregulates ERV transcription, driving a similar effect to that seen with irradiation. Furthermore, KAP1 depletion is sufficient to inhibit tumor growth of B16F10 tumors in in vivo studies, but this effect is dependent on an intact host immune system. Tumor growth inhibition in vivo is driven by increased recruitment of immune cells to the tumor microenvironment, along with upregulated of interferon-stimulated genes. Patient data support our findings, as mRNA analysis of TCGA patient cohorts reveals that Trim28 expression is negatively associated with survival and immune recruitment. Taken as a whole, our work indicates KAP1 as a crucial modulator of ERVs, with significant consequences for cancer therapy.